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HOWELL RESEARCH GROUP DEPARTMENT
OF CHEMISTRY |
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Glycosphingolipids
Interest
in glycosphingolipids has increased in recent years, in part due to
the recognition that they modulate immune responses. For example, KRN7000,
an alpha-galactosyl ceramide, has been shown to be a potent activator
of the immune system. KRN7000 has been shown to bind to the CD1 family
of antigen presenting proteins. The CD1 family has been implicated in
such worldwide diseases as multiple sclerosis, malaria, hepatitis B
and cancer. We have established a variety of collaborations with immunologists
working in the CD1 area to examine the potential of glycosyl ceramides
for the treatment of autoimmune conditions and other CD1 related diseases.
Our current approach to glycosphingolipids containing aminodiol sphingoid
bases (e.g. 18) is shown in Scheme 3. We have shown
that 18 is as active as KRN7000. As 18
is much easier to prepare, this result should increase the number of
analogs we can prepare. |
Alternatively,
glycosphingolipids can be accessed by first coupling the protected sphingoid
base 19 with a sugar. Then, N-acylation of 20
provides glycosphingolipids (Scheme 4). The advantage of this strategy
is that various glycosphingolipids can be synthesized by attaching different
acid chains to the free amine. In addition we have provided galactosphingosine
20 to some of our collaborators for the preparation
of focused combinatorial libraries. |
| Our approach to aminotriol sphingoid bases (e.g. 21), is shown in Scheme 5. These strategies will give access to diverse glycosphingolipids and should improve our understanding of how these compounds interact with the immune system. |
